Preparation of 7-(3-amino- and 3-amino-methyl-1-pyrrolidinyl)-3-quinolonecarboxylic acids and -naphthridonecarboxylic acids

ABSTRACT

Process for the preparation of antibacterial compounds of the formula ##STR1## comprises condensing an oxo compound of the formula ##STR2## with an amino compound of the formula ##STR3## to produce a compound of the formula ##STR4## reacting the compound of the formula (III) with a compound of the formula ##STR5## to give a compound of the formula ##STR6## and then eliminating the amino-protective group ##STR7##

This is a division of application Ser. No. 07/717/748 filed on Jun. 19,1991 (U.S. Pat. No. 5,648,493), which is a division of application Ser.No. 07/529,016, filed on May 25, 1990 (now U.S. Pat. No. 5,061,712).

The present invention relates to a process for the preparation of7-(3-amino- and 3-aminomethyl-1-pyrrolidinyl)-3-quinolonecarboxylicacids and -naphthyridonecarboxylic acids which have been disclosed asantibacterial agents and are prepared by reaction of7-halogeno-3-quinolonecarboxylic acids or -naphthyridonecarboxylic acidswith 3-aminopyrrolidine or 3-aminomethylpyrrolidine in free form or inthe form of the 3-acylamino- or 3-acylaminomethyl-pyrrolidines andsubsequent elimination of the acyl radicals. Reactions of this type havebeen described, for example, in the following patent applications:

European Patent Applications 153,163, 183,129, 195,316, 198,678,200,307, 207,497 and 236,673; U.S. Pat. No. 4,550,104; and JapanesePatent Application 63,166,876.

However, these processes have various disadvantages:

1. If 3-amino- or 3-aminomethylpyrrolidones in which the amino group isnot protected by an acyl radical are employed, the reaction with7-halogenoquinolonecarboxylic acids does not proceed selectively in thedesired sense by substitution on the pyrrolidine nitrogen, but thepresence of the free amino group also leads to the occurrence ofby-products which would have to be removed by expensive purification.

2. If 3-acylamino- or 3-acylaminomethylpyrrolidines in which acetyl ortert.-butoxycarbonyl is usually used as the acyl radical are employed,the reactions proceed selectively on the pyrrolidine nitrogen to givethe 7-(3-acylamino- or3-acylaminomethyl-1-pyrrolidinyl)-3-quinolonecarboxylic acids. Toprepare the free 7-(3-amino- or3-aminomethyl-1-pyrrolidinyl)-3-quinolonecarboxylic acids, subsequentelimination of the protective group by treatment with aqueous sodiumhydroxide solution under the influence of heat or with hydrochloric acidor trifluoroacetic acid is required. This can again lead to undesirableside reactions: for example the highly active 8-bromo- or8-chloro-3-quinolonecarboxylic acids can in some cases lose the halogenatom in the 8-position during deblocking with hydrochloric acid.

In order to avoid these disadvantages, it was necessary to develop aprocess which makes it possible to prepare 7-(3-amino-and3-aminomethyl-1-pyrrolidinyl)-3-quinolonecarboxylic acids in a highpurity in a simple manner.

It has been found that the compounds of the formula (I), which can existas enantiomeric or diastereomeric mixtures or in the enantiomerically ordiastereomerically pure form ##STR8## and in which X¹ representshydrogen, amino, alkylamino having 1 to 4 carbon atoms, dialkylaminohaving 1 to 3 carbon atoms per alkyl group, hydroxyl, alkoxy having 1 to4 carbon atoms, mercapto, alkylthio having 1 to 4 carbon atoms,arylthio, halogen or alkyl having 1 to 4 carbon atoms,

R¹ represents straight-chain or branched alkyl having 1 to 5 carbonatoms, which can optionally be substituted by 1 to 3 halogen atoms, oralkenyl having 2 to 4 carbon atoms, cycloalkyl having 3 to 6 carbonatoms, 2-hydroxyethyl, methoxy, amino, methylamino, ethylamino,dimethylamino or phenyl which is optionally substituted by 1 or 2fluorine atoms,

R² represents hydrogen, alkyl having 1 to 4 carbon atoms or(5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl,

R³ represents hydrogen, C₁ -C₃ -alkyl, hydroxyl, C₁ -C₃ -alkoxy, C₁ -C₃-alkylthio or halogen,

R⁴ represents hydrogen or methyl,

R⁵ and R⁶ are identical or different and represent hydrogen or methyl,

m represents 0, 1 or 2,

n represents 0 or 1 and

A represents N or C--R⁷, wherein

R⁷ represents H, halogen, methyl, cyano, nitro, hydroxyl or methoxy, ortogether with R¹ can also form a bridge having the structure --O--CH₂--CH--CH₃, --S--CH₂ --CH--CH₃ or --CH₂ --CH₂ -CH--CH₃ which can have theR- or S-configuration,

are obtained by a process in which compounds of the formula (II)##STR9## in which X¹, R¹, R² and A have the abovementioned meaning and

X² represents halogen,

are reacted with compounds of the formula (III) ##STR10## in which R³,R⁴, R⁵, R⁶, m and n have the abovementioned meanings,

R' represents hydrogen, straight-chain or branched alkyl having 1 to 10carbon atoms or phenyl, which can optionally be substituted by one tofive identical or different substituents from the group comprising C₁-C₄ -alkyl, C₁ -C₄ -alkoxy, C₁ -C₂ -alkylthio, hydroxyl, nitro, halogen,carboxyl, C₁ -C₄ -alkoxycarbonyl, cyano and phenyl, or representsnaphthyl, and

R" represents hydrogen, straight-chain or branched alkyl having 1 to 5carbon atoms or phenyl, wherein R' and R", together with the carbon atomto which they are bonded, can also form a 5- or 6-membered aliphaticring which is optionally substituted by one or more methyl or ethylradicals,

if appropriate in the presence of an acid-binding agent, to givecompounds of the formula (IV) ##STR11## in which X¹, A, R¹, R², R³, R⁴,R⁵, R⁶, R', R", m and n have the abovementioned meanings, and theamino-protective group is then eliminated.

Compounds which are preferred for the process according to the inventionare those of the formula (II) ##STR12## in which X¹ represents hydrogen,amino, hydroxyl, alkoxy having 1 or 2 carbon atoms, fluorine, chlorine,bromine or alkyl having 1 to 3 carbon atoms,

X² represents fluorine or chlorine,

R¹ represents straight-chain or branched alkyl having 1 to 4 carbonatoms, which can optionally be substituted by 1 to 3 fluorine atoms, oralkenyl having 2 to 3 carbon atoms, cycloalkyl having 3 or 4 carbonatoms, 2-hydroxyethyl, 2-fluoroethyl, methylamino, ethylamino,dimethylamino or phenyl which is optionally substituted by 1 or 2fluorine atoms,

R² represents hydrogen or alkyl having 1 to 3 carbon atoms and

A represents N or C--R⁷, wherein

R⁷ represents H, fluorine, chlorine, bromine, methyl, hydroxyl ormethoxy, or together with R¹ can also form a bridge having the structure--O--CH₂ --CH--CH₃,

and those of the formula (III) ##STR13## in which R³ representshydrogen, methyl, ethyl, hydroxyl, methoxy, ethoxy, methylthio,ethylthio, chlorine or fluorine,

R⁴ represents hydrogen or methyl,

R⁵ represents hydrogen,

R⁶ represents hydrogen,

m represents 0 or 1,

n represents 0 or 1,

R' represents hydrogen, straight-chain or branched alkyl having 1 to 6carbon atoms or phenyl, which can optionally be substituted by 1 to 5identical or different substituents from the group comprising methyl,methoxy, ethoxy, hydroxyl, nitro, fluorine, chlorine, carboxyl, C₁ -C₃-alkoxycarbonyl and cyano, and

R" represents hydrogen, straight-chain or branched alkyl having 1 to 4carbon atoms or phenyl, wherein R' and R", together with the carbon atomto which they are bonded, can also form a 5- or 6-membered aliphaticring.

Compounds which are particularly preferred for the process according tothe invention are those of the formula (II) ##STR14## in which X¹represents hydrogen, amino, methoxy, fluorine, chlorine or methyl,

X² represents fluorine or chlorine,

R¹ represents methyl, ethyl, tert.-butyl, vinyl, cyclopropyl,2-fluoroethyl, 4-fluorophenyl or 2,4-difluorophenyl,

R² represents hydrogen, methyl or ethyl and

A represents N or C--R⁷, wherein

R⁷ represents hydrogen, fluorine, chlorine, methyl or methoxy, ortogether with R¹ can also form a bridge having the structure --O--CH₂--CH--CH₃,

and those of the formula (III) ##STR15## in which R³ representshydrogen, methyl, hydroxyl, methoxy, methylthio, ethylthio or fluorine,

R⁴ represents hydrogen or methyl,

R⁵ represents hydrogen,

R⁶ represents hydrogen,

m represents 0 or 1,

n represents 0 or 1,

R' represents hydrogen, straight-chain or branched alkyl having 1 to 5carbon atoms or phenyl, which can optionally be substituted by 1 to 4identical or different substituents from the group comprising methyl,methoxy, hydroxyl, nitro, fluorine, chlorine, carboxyl and C₁ -C₂-alkoxycarbonyl, and

R" represents hydrogen, straight-chain or branched alkyl having 1 to 3carbon atoms or phenyl, wherein R' and R", together with the carbon atomto which they are bonded, can also form a 5- or 6-membered aliphaticring.

The invention likewise relates to compounds of the formulae (III) and(IV), although compounds of the formula (IV) in which, simultaneously,R" represents H, n represents 0, m represents 1, R³ and R⁴ represent H,X¹ represents H, A represents CH, R² represents H or acarboxyl-protective group, R¹ represents C₁ -C₅ -alkyl, cyclopropyl orphenyl which is optionally substituted by 1 or 2 fluorine atoms and R'represents phenyl or substituted phenyl are excluded.

The compounds of the formula (II) used as starting substances are knownor can be prepared by known methods. Examples which may be mentionedare:

7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (U.S. application Ser. No. 436,112 filed Oct. 22, 1982, nowabandoned, corresponding to German Application 3,142,854)

1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid(European Patent Application 113,091),

8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (U.S. application Ser. No. 735,500 filed May 17, 1985, now pending,corresponding to German Application 3,420,743

1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (U.S. Pat. No. 4,556,658)

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylicacid,

6,7-difluoro-1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

7-chloro-6-fluoro-1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

7-chloro-6-fluoro-1,4-dihydro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylicacid,

1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylicacid,

6,7-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

6,7-difluoro-1,4-dihydro-1-methoxy-4-oxo-3-quinolinecarboxylic acid,

6,7-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid,

6,7-difluoro-1,4-dihydro-4-oxo-1-phenyl-3-quinolinecarboxylic acid,

6,7-difluoro-1-(4-fluoro-phenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

6,7-difluoro-1-(3,4-difluoro-phenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

ethyl1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate(U.S. Pat. No. 4,556,658)

9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido- 1,2,3-de!1,4!benzoxazine-6-carboxylic acid (European Patent Application 47,005)and the R- or S-form thereof (U.S. Ser. No. 939,582 filed Dec. 9, 1986,now pending, corresponding to German Application 3,543,513)

8,9-difluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzoi,j!-quinolizine-2-carboxylic acid,

7-chloro-6-fluoro-1-phenyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (European Patent Application 153,580),

7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (European Patent Application 153,580),

6,7,8-trifluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylicacid (U.S. Pat. No. 4,666,920)

1-amino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid(U.S. Pat. No. 4,666,920)

6,7,8-trifluoro-1,4-dihydro-1-dimethylamino-4-oxo-3-quinolinecarboxylicacid (U.S. Pat. No. 4,666,920)

7-chloro-6-fluoro-1,4-dihydro-8-nitro-4-oxo-1-phenyl-3-quinolinecarboxylicacid,

7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylicacid,

6,7-difluoro-1-(4-fluorophenyl)-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylicacid,

6-chloro-7-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (European Patent Application 131,839),

6-chloro-7-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (European Patent Application 131,839),

6,7,8-trifluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (European Patent Application 154,780),

6,7,8-trifluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (European Patent Application 154,780),

6,7,8-trifluoro-1,4-dihydro-4-oxo-1-phenyl-3-quinolinecarboxylic acid(European Patent Application 154,780),

7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

6,7-difluoro-1,4-dihydro-4-oxo-1-vinyl-3-quinolinecarboxylic acid,

1-tert.-butyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

1-tert.-butyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

1-tert.-butyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid and

ethyl7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridin-3-carboxylate.

The intermediate compounds of the formula (III) are novel. They areprepared by condensation of an oxo compound of the formula (V) with anamino compound of the formula (VI), water being eliminated. ##STR16##

Chiral amino compounds of the formula (VI) can be employed either asracemates or as enantiomerically pure or diastereomerically purecompounds.

The reaction of (V) with (VI) is carried out either without a diluent orin a diluent, such as, for example, acetonitrile, dimethylformamide,dimethylsulphoxide, sulpholane, an alcohol, such as methanol, ethanol,propanol or isopropanol, an ether, such as diethyl ether, diisopropylether, glycol monomethyl ether, tert.-butyl methyl ether, dioxane ortetrahydrofuran, an aromatic or aliphatic hydrocarbon, such as toluene,xylene, chlorobenzene, methylene chloride, pentane, hexane orcyclohexane, or pyridine. Mixtures of these diluents can also be used.

The reaction of (V) with (VI) is usually carried out without furtheradditives. However, it is also possible to add catalytic amounts of aninorganic or organic acid, such as sulphuric acid, hydrochloric acid,benzenesulphonic acid, p-toluenesulphonic acid or an acid ion exchanger.Sodium sulphate, magnesium sulphate, calcium chloride or a molecularsieve can be added as a water-binding agent. The reaction can also becarried out in an apparatus which separates off water.

The reaction temperatures can be varied within a substantial range. Thereaction is in general carried out between about -20° C. and 120° C.,preferably between 0° C. and 50° C.

The reaction can be carried out under normal pressure or under increasedpressure. It is in general carried out under pressures between about 1bar and about 10 bar, preferably under normal pressure.

The compounds of the formula (III) can be isolated from the reactionmixture, for example by fractional distillation.

However, the compounds of the formula (III) can also advantageously bereacted with the compounds of the formula (II) in a one-pot processwithout intermediate isolation, to give compounds of the formula (I).This in situ preparation is particularly appropriate if the compounds ofthe formula (III) are difficult to isolate, such as, for example, in thereaction of 3-aminopyrrolidine with aromatic aldehydes. On the otherhand, the isolation of the intermediate product of the formula (III) maybe advantageous if the amino component (VI) has to be isolated from areaction mixture. For example, if 3-aminopyrrolidine is prepared byhydrogenolytic debenzylation of 1-benzyl-3-benzylamino-pyrrolidine, thecrude reaction solution can be reacted with pivalaldehyde withoutintermediate isolation of the 3-aminopyrrolidine, and the3-(2,2-dimethyl-propylideneamino)-pyrrolidine can be isolated in asimple manner.

The process according to the invention, that is to say the protection ofthe amino compounds of the formula (VI) by a carbonyl compound of theformula (V) and the subsequent selective reaction of the reactionproduct (III) with 7-halogenoquinolonecarboxylic acids of the formula(II), is to be regarded as exceptionally surprising inasmuch as it isknown from the literature that aldehydes form cyclic or bicyclic aminalswith open-chain or cyclic diamines see, for example, DE 2,739,313; J.Amer. Chem. Soc. 95, 3362 (1973); J. Org. Chem. 53 420 (1988); LiebigsAnn. Chem. 1977, 956 and Eur. J. Med. Chem. 17, 235 (1982)!. Aldehydescan therefore be protected with diamines in organometallic reactionsAust. J. Chem. 26, 1363 (1973) and Tetrahedron 41, 3803 (1985)!.

In view of these publications, it had to be expected that, for example,3-amino-pyrrolidine reacts with aldehydes to give bicyclic aminals:##STR17##

It was therefore to be expected that the bicyclic aminals would reactwith 7-halogeno-4-quinolone-3-carboxylic acids or-naphthyridone-carboxyiic acids of the formula (II) on the secondaryrather than on the tertiary nitrogen atom and after elimination of theprotective group would lead to 7-(pyrrolidin-3-yl-amino)-quinolone- or-naphthyridone-3-carboxylic acids, so that the specific reaction to give7-(3-amino-1-pyrrolidinyl)-4-quinolone-3-carboxylic acids or-naphthyridone-carboxylic acids of the formula (I) is surprising.

If, for example,1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid is reacted with 3-(2,2-dimethylpropylideneamino)-pyrrolidine andthe reaction product is treated with hydrochloric acid,7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride is obtained.

The reaction can be represented by the following equation: ##STR18##

If, for example, the reaction mixture of 3-nitrobenzaldehyde and(S)-3-aminopyrrolidine is reacted with8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid in a one-pot reaction, the course of the reaction via theintermediately formed 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(S)-3-(3-nitrobenzylideneamino)-1-pyrrolidinyl!-4-oxo-3-quinolinecarboxylicacid to give 7-(S)-3-amino-1-pyrrolidinyl!-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride can be represented by the following equation:##STR19##

The starting compounds of the formula (V) are known. The followingcompounds may be mentioned as examples:

Benzaldehyde, 2-chlorobenzaldehyde, 3-chlorobenzaldehyde,4-chlorobenzaldehyde, 2,4-dichlorobenzaldehyde,2,6-dichlorobenzaldehyde, 2,4,5-trichlorobenzaldehyde,2-nitrobenzaldehyde, 3-nitrobenzaldehyde, 4-nitrobenzaldehyde,4-chloro-3-nitrobenzaldehyde,

2-chloro-5-nitrobenzaldehyde, 2-methylbenzaldehyde,3-methylbenzaldehyde, 4-methylbenzaldehyde, 3-phenylpropionaldehyde,cinnamaldehyde, 2-, 3- and 4-hydroxybenzaldehyde,3,5-dichloro-2-hydroxybenzaldehyde, 2-hydroxy-1-naphthaldehyde,2-hydroxy-3-methoxy-benzaldehyde, 4-hydroxy-3-methoxy-benzaldehyde, 2-,3- and 4-methoxybenzaldehyde, 2-, 3- and 4-pyridinecarboxaldehyde,2-fluorobenzaldehyde, 4-fluorobenzaldehyde, 3-fluorobenzaldehyde,2,4-difluorobenzaldehyde, 3,5-difluorobenzaldehyde, acetaldehyde,propionaldehyde, butyraldehyde, 2-methylbutanal, 2,2-dimethyl-propanal,trichloroacetaldehyde hydrate (chloral hydrate), glyoxal, acetone,butanone, 3-methyl -2-butanone, cyclohexanone and cyclopentanone.

Instead of the oxo compounds (V), it is also possible to use derivativeswhich behave like oxo compounds under the reaction conditions, such as,for example, acetals or ketals.

The following compounds may be mentioned as examples of startingcompounds of the formula (VI), it being possible for chiral compounds tobe employed either as racemates or as enantiomerically pure ordiastereomerically pure substances:

(R,S)-3-amino-pyrrolidine,

(R)-3-amino-pyrrolidine,

(S)-3-amino-pyrrolidine,

cis- and trans-3-amino-4-methoxy-pyrrolidine,

3-amino-2-methyl -4-methoxy-pyrrolidine,

4-amino-2-methyl-3-methoxy-pyrrolidine,

cis- and trans-3-amino-4-methyl-pyrrolidine,

3-amino-3-methyl-pyrrolidine,

3-amino-2-methyl-pyrrolidine,

4-amino-2-methyl-pyrrolidine,

3-aminomethyl-pyrrolidine,

3-aminomethyl-3-hydroxy-pyrrolidine,

3-aminomethyl-3-methoxy-pyrrolidine,

3-aminomethyl-3-methyl-pyrrolidine,

4-amino-2-hydroxymethyl-pyrrolidine,

3-(1-aminoethyl)-pyrrolidine,

3-amino-azetidine,

3-aminomethyl-azetidine,

3-amino-piperidine,

4-amino-piperidine,

cis- and trans-3-amino-4-methylthio-pyrrolidine and

cis- and trans-3-amino-4-ethylthio-pyrrolidine.

The reaction of (II) with (III) is preferably carried out in a diluent,such as dimethyl sulphoxide, N,N-dimethylformamide, N-methylpyrrolidone,hexamethylphosphoric acid triamide, sulpholane, acetonitrile, water, analcohol, such as methanol, ethanol, n-propanol or isopropanol, glycolmonomethyl ether or pyridine. Mixtures of these diluents can likewise beused, or the diluent can be dispensed with entirely.

Acid-binding agents which can be used are all the customary inorganicand organic acid-binding agents. These include, preferably, the alkalimetal hydroxides, alkali metal carbonates, organic amines and amidines.Particularly suitable acid-binding agents which may be mentionedspecifically are: triethylamine, 1,4-diazabicyclo 2.2.2!octane(DABCO),1,8-diazabicyclo 5.4.0!undec-7-ene (DBU) or excess amine (III).

The reaction temperatures can be varied within a substantial range. Thereaction is in general carried out between about 20 and 200° C.,preferably between 60° C. and 150° C.

The reaction can be carried out under normal pressure or under increasedpressure. It is in general carried out under pressures between about 1and 100 bar, preferably between 1 and 10 bar.

In carrying out the process according to the invention, 1 to 5 mols,preferably 1 to 3 mols, of the compound (III) are preferably employedper mol of carboxylic acid (II).

The intermediate compound (IV) formed in the reaction of (II) with (III)does not have to be isolated in pure form. Hydrolytic elimination of theoxo compound (V) from the intermediate compound (IV) often alreadyproceeds during work up in the presence of water at room temperature. Itcan be accelerated by heating. Under these conditions, the reactionproduct of the formula (I) is isolated as the betaine.

It is advantageous, after isolation of the intermediate compound (IV),to carry out the elimination of the protective group in the presence ofequivalent or excess amounts of an acid, it being possible for thereaction product (I) to be isolated in the form of the salt of thisacid. Examples of possible acids are hydrochloric acid, sulphuric acid,acetic acid, trifluoroacetic acid, lactic acid, glycolic acid, succinicacid, citric acid, tartaric acid, methanesulphonic acid,p-toluenesulphonic acid, nicotinic acid, galacturonic acid, gluconicacid, embonic acid, glutamic acid or aspartic acid.

The eliminated oxo compound (V) can be re-isolated from the reactionbatch in a simple manner by extraction with a solvent, such as, forexample, methylene chloride, diethyl ether, toluene, ethyl acetate ortert.-butyl methyl ether, and can be fed into the reaction again, whichleads to a further simplification and reduction in the costs of thereaction.

The possibility of gentle elimination in a two-phase system of aqueousdilute acid and a water-immiscible extraction agent which dissolves theoxo compound (V) and thus removes it from the reaction solution is ofgreat advantage for quinolonecarboxylic acids containing sensitiveradicals.

Thus, for example, 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-3-(3-nitrobenzylideneamino)-1-pyrrolidinyl !-4-oxo-3-quinolinecarboxylicacid can be smoothly deblocked with 3N hydrochloric acid in the courseof 15 minutes without noticeable 8-deschlorination being observed. Incontrast, on deblocking of7-(3-tert.-butoxycarbonylamino-1-pyrrolidinyl)-3-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid with 3N hydrochloric acid under these conditions, elimination ofthe protective group takes place to the extent of only about 10% evenafter 30 minutes, the cleavage product already being contaminated by7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (8-deschloro derivative).

In addition to the active compounds listed in the examples, thefollowing compounds, which can be present as racemates or asenantiomerically pure substances in the form of salts (for example asthe hydrochloride, sulphate, methanesulphonate, p-toluenesulphonate oracetate) can be prepared by the process according to the invention:

    ______________________________________                                         ##STR20##                                                                    R.sup.1      R.sup.3 X.sup.1    A    n                                        ______________________________________                                         ##STR21##   H       H          N    0                                         ##STR22##   H       H          N    1                                         ##STR23##   CH.sub.3 O                                                                            H          N    0                                         ##STR24##   CH.sub.3 S                                                                            H          N    0                                         ##STR25##   H       H          N    0                                         ##STR26##   CH.sub.3 O                                                                            H          N    0                                         ##STR27##   CH.sub.3 S                                                                            H          N    0                                        (CH.sub.3).sub.3 C                                                                         H       H          N    0                                        (CH.sub.3).sub.3 C                                                                         CH.sub.3 O                                                                            H          N    0                                        (CH.sub.3).sub.3 C                                                                         CH.sub.3 S                                                                            H          N    0                                         ##STR28##   H       NH.sub.2   CF   0                                         ##STR29##   H       CH.sub.3   CF   0                                         ##STR30##   H       CH.sub.3   CH   0                                         ##STR31##   H       NH.sub.2   CF   1                                         ##STR32##   H       NH.sub.2   CH   0                                         ##STR33##   H       CH.sub.3   CF   1                                         ##STR34##   H       F          CF   0                                         ##STR35##   CH.sub.3                                                                              H          CH   0                                         ##STR36##   CH.sub.3                                                                              H          CF   0                                         ##STR37##   CH.sub.3                                                                              H          CCl  0                                         ##STR38##   CH.sub.3                                                                              H          N    0                                        ______________________________________                                    

10-(3-amino-1-pyrrolidinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido1,2,3-de! 1,4!benzoxazine-6-carboxylic acid and10-(3(S)-amino-1-pyrrolidinyl)-9-fluoro-2,3-dihydro-3(S)-methyl-7-oxo-7H-pyrido1,2,3-de! 1,4!benzoxazine-6-carboxylic acid.

The intermediate compounds of the formula (IV) exhibit a broad spectrumof antibacterial activity against Gram-positive and Gram-negative germs,in particular against Enterobacteriaceae; above all also against thosewhich are resistant towards various antibiotics, such as, for example,penicillins, cephalosporins, aminoglycosides, sulphonamides andtetracyclines, coupled with a low toxicity.

These useful properties make it possible to use them as chemotherapeuticactive compounds in medicine and as substances for preserving inorganicand organic materials, in particular all types of organic materials, forexample polymers, lubricants, paints, fibers, leather, paper and wood,and foodstuffs and water.

The compounds (IV) according to the invention are active against a verybroad spectrum of microorganisms. With the aid of these compounds,Gram-negative and Gram-positive bacteria and bacteria-likemicroorganisms can be combated and the diseases caused by thesepathogens can be prevented, alleviated and/or cured.

The compounds (IV) according to the invention are particularly activeagainst bacteria and bacteria-like microorganisms. They are thereforeparticularly suitable in human and veterinary medicine for theprophylaxis and chemotherapy of the local and systemic infections causedby these pathogens.

For example, local and/or systemic diseases which are caused by thefollowing pathogens or by mixtures of the following pathogens can betreated and/or prevented: Gram-positive cocci, for example Staphylococci(Staph. aureus and Staph. epidermidis) and Streptococci (Strept.agalactiae, Strept. faecalis, Strept. pneumoniae and Strept. pyogenes);Gram-negative cocci (Neisseria gonorrhoeae) and Gram-negative rod-shapedbacilli, such as Enterobacteriaceae, for example Escherichia coli,Haemophilus influenzae, Citrobacter (Citrob. freundii and Citrob.divernis), Salmonella and Shigella; and furthermore Klebsiellae (Klebs.pneumoniae and Klebs. oxytoca), Enterobacter (Ent. aerogenes and Ent.agglomerans), Hafnia, Serratia (Serr. marcescens), Proteus (Pt.mirabilis, Pr. rettgeri and Pr. vulgaris), Providencia, Yersinia and thegenus Acinetobacter. The antibacterial spectrum moreover includes thegenus Pseudomonas (Ps. aeruginosa and Ps. maltophilia) and strictlyanaerobic bacteria, such as, for example, Bacteroides fragilis,representatives of the genus Peptococcus, Petrostreptococcus and thegenus Clostridium; and furthermore Mycoplasma (M. pneumoniae, M. hominisand M. urealyticum) as well as Mycobacteria, for example Mycobacteriumtuberculosis.

The following examples document the invention:

EXAMPLE A

3-(2,2-Dimethyl-propylidene-amino)-pyrrolidine

1. 34.5 g (0.4 mol) of 3-aminopyrrolidine are initially introduced into100 ml of toluene, and 34.5 g (0.3 mol) of 75% strength pivalaldehyde(preparation from Riedel-de-Haen) in 100 ml of toluene are addeddropwise at 20° C., while cooling in a water bath. The mixture issubsequently stirred at room temperature for 2 hours, the aqueous phaseis then separated off in a separating funnel (4.6 ml) and the toluenesolution is dried over sodium sulphate for 1 hour. The toluene isseparated off on a rotary evaporator and the residue is distilled usinga small Vigreux column. 46.2 g of3-(2,2-dimethylpropylideneamino)-pyrrolidine of boiling point 61° C./10mbar are obtained with a purity, determined by gas chromatography, of98%, corresponding to a yield of 74% and a selectivity of 99%(pivalaldehyde).

2. 8.6 g (0.1 mol) of 3-aminopyrrolidine are initially introduced intothe reaction vessel and 8.8 g (0.1 mol) of 97% strength pivalaldehyde(preparation from Aldrich) are added dropwise at 20° C. to 30° C., whilecooling in a water bath. The mixture is subsequently stirred at roomtemperature for 1 hour and is then distilled.

Yield: 13.1 g (85% of theory),

boiling point: 60°-63° C./10 mbar; content: 99%.

3. 12.1 g (0.1 mol) of 71% strength pivalaldehyde, initially introducedinto the reaction vessel and 8.6 g (0.1 mol) of 3-aminopyrrolidine areadded dropwise at 20° C. to 30° C., while cooling in a water bath. Themixture is subsequently stirred at room temperature for 1 hour and isthen distilled. Yield: 13.5 g (85% of theory), boiling point: 63° C.-65°C./10 to 12 mbar; content: 97%.

EXAMPLES A 4-9

8.6 g (0.1 mol) of 3-aminopyrrolidine are initially introduced into thereaction vessel, if appropriate in 50 ml of solvent, and pivalaldehydeis added dropwise at 20° C. to 30° C., while cooling in a water bath.The mixture is subsequently stirred at room temperature for 1 hour, anaqueous phase is separated off if appropriate, the solvent is removed ona rotary evaporator and the crude product is distilled.

    ______________________________________                                                           3-(2,2-Dimethyl-propyl-                                                       ideneamino)-pyrrolidine                                    Ex-    Pival-                           Yield or                              ample  aldehyde              Content    selectivity                           A       mol!    Solvent       %!    g!   %!                                   ______________________________________                                        4      0.1      THF          98    12.5 79                                    5      0.1      --           97    13.0 82                                    6      0.09     --           94    13.9 94                                    7      0.12     --           96    13.5 84                                    8      0.09     CH.sub.3 OH  95    13.1 90                                    9      0.09     CH.sub.3 --O--C(CH.sub.3).sub.3                                                            95    13.7 94                                    ______________________________________                                    

10. 36.8 g (0.138 mol) of 1-benzyl-3-benzylaminopyrrolidine arehydrogenated in 160 ml of methanol over 5 g of 5% strength palladium onactive charcoal at 130° C. under a hydrogen pressure of 100 bar for 10hours. The catalyst is filtered off and 16.6 g (0.138 mol ) of 71%strength pivalaldehyde are added to the filtrate, while stirring, afterwhich the temperature rises from 20° C. to 28° C. The mixture issubsequently stirred for 30 minutes, the methanol is removed on a rotaryevaporator and the residue is distilled. 12.7 g of3-(2,2-dimethyl-propylidene-amino)-pyrrolidine of boiling point: 61°C./10 mbar are obtained with a purity, determined by gas chromatography,of 97%, corresponding to a yield of 58% of theory.

EXAMPLE B

3-(3,5-Difluorobenzylidene-amino)-pyrrolidine ##STR39##

1.72 g (20 mmol) of 3-amino-pyrrolidine are initially introduced into 20ml of methanol, and 2.84 g (20 mmol) of 3,5-difluorobenzaldehyde areadded dropwise at 20° C., whale cooling in a water bath. The mixture issubsequently stirred at room temperature for one hour and isconcentrated in vacuo on a rotary evaporator, and the residue (4.5 g) isdistilled. 0.9 g of an oil, boiling point: 80° C.-85° C./0.04 mbar, areobtained, which decomposes to give a highly viscous mass within 4 weekswhen stored at room temperature.

EXAMPLE C

3- (2,2-Dimethylpropylideneamino)-methyl!-pyrrolidine

2.0 g (20 mmol) of 3-aminomethyl-pyrrolidine are initially introducedinto 10 ml of methanol, and 1.8 g (22 mmol) of 97% strengthpivalaldehyde are added dropwise at room temperature, after which theinternal temperature rises to 30° C. The mixture is subsequently stirredfor 1 hour and then concentrated, and the residue is distilled through aVigreux column.

Yield: 2.8 g (80% of theory) of 97% pure product;

boiling point: 84°-88° C./11 to 13 mbar.

EXAMPLE D

(R)-3-(2,2-Dimethyl-propylideneamino)-pyrrolidine

Analogously to Example A-1, the reaction is carried out with(R)-3-aminopyrrolidine to give(R)-3-(2,2-dimethyl-propylideneamino)-pyrrolidine of boiling point 62°C./8 mbar;

α_(D) ²⁰ =+36.3° (c=1.002, CHCl₃).

EXAMPLE E

(S)-3-(2,2-Dimethyl-propylideneamino)-pyrrolidine

Analogously to Example A-1, the reaction is carried out with(S)-3-aminopyrrolidine to give(S)-3-(2,2-dimethyl-propylideneamino)-pyrrolidine of boiling point 61°C./10 mbar;

α_(D) ²⁰ =-36.5° (c=1.0, CHCl₃).

EXAMPLE F

a) 1-Benzoyl-trans-3-amino-4-methylthio-pyrrolidine

41.5 g (0.24 mol) of 1-benzoyl-2,5-dihydropyrrole are initiallyintroduced into 240 ml of methylene chloride, and 24.8 g (0.3 mol) ofmethanesulphonyl chloride are added dropwise at 0° C. The mixture issubsequently stirred at room temperature for 16 hours, the solvent isthen stripped off under 8 mbar and the residue is taken up in 240 ml oftetrahydrofuran. After addition of 65 g of 25% strength ammoniasolution, the mixture is heated at 80° C. in an autoclave for 10 hours.It is then poured into 5 times the amount of water, the pH is brought to10-11 with sodium carbonate, the mixture is extracted with methylenechloride and the extract is dried over sodium sulphate and concentrated.The crude product (50 g) is chromatographed on silica gel (mobile phaseinitially ethanol:ethyl acetate 1:3, then ethanol; Rf value: 0.34ethanol).

Yield: 33.5 g (59% of theory).

b) trans-3-Amino-4-methylthio-pyrrolidine

23.6 g (0.1 mol) of 1-benzoyl-trans-3-amino-4-methylthio-pyrrolidine arestirred with 80 ml of 5N sodium hydroxide solution until a homogeneoussolution has formed (2 hours). The solution is then saturated withsodium sulphate and extracted with tert.-butyl methyl ether in aperforator. The extract is dried over sodium sulphate, filtered andconcentrated and the residue is distilled.

Yield: 10.5 g (79% of theory), boiling point: 108°-110° C./11 mbar.

c) trans-3-(2,2-Dimethyl-propylideneamino)-4-methylthio-pyrrolidine

1.32 g (10 mmol) of trans-3-amino-4-methylthio-pyrrolidine are initiallyintroduced into 5 ml of methanol, and 1.23 ml (11 mmol) of 97% strengthpivalaldehyde are added dropwise, after which the temperature rises from25° to 36° C. The mixture is subsequently stirred for a further 30minutes, without cooling, the batch is then concentrated and the residueis distilled. Yield: 1.50 g (75% of theory),

boiling point: 63° C./0.07 mbar.

EXAMPLE 1 ##STR40##

3 g (10 mmol) of8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid are heated under reflux with 2.2 (20 mmol) of 1,4-diazabicyclo2.2.2!octane and 1.7 g (11 mmol) of3-(2,2-di-methylpropylideneamino)-pyrrolidine in a mixture of 20 ml ofacetonitrile and 10 ml of dimethylformamide for 1 hour. The mixture isconcentrated in vacuo, the residue is stirred with water and theundissolved residue is filtered off with suction, washed with water anddried at 70° C. in vacuo. The resulting product is recrystallized from amixture of 35 ml of glycol monomethyl ether and 5 ml ofdimethylformamide and washed with ethanol.

Yield: 3.2 g (87.6% of theory) of7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4dihydro-4-oxo-3-quinolinecarboxylicacid;

melting point: 254°-256° C. (with decomposition); content: 100% pure(according to HPLC).

EXAMPLE 2 ##STR41##

a) A mixture of 0.86 g (10 mmol) of 3-aminopyrrolidine, 1.8 g ofmolecular sieve (4 Å) and 0.95 g (11 mmol) of pivalaldehyde in 10 ml ofacetonitrile is stirred at room temperature for 1 hour, with exclusionof moisture, the solution is decanted off from the molecular sieve andrinsed with 10 ml of acetonitrile, and 10 ml of dimethylformamide areadded. 3 g (10 mmol) of8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-3-quinolinecarboxylicacid and 2.2 g (20 mmol) of 1,4-diazabicyclo- 2.2.2!octane are thenadded and the mixture is heated under reflux for 1 hour. It isevaporated, the residue is stirred with water (pH 7) and the precipitateis filtered off with suction, washed with water and dried.

Yield: 3.2 g (87.6% of theory) of7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid; recrystallization from dimethylformamide gives 2.7 g of theproduct of melting point 235° C. (with decomposition); content: 98.9%(according to HPLC).

b) 0.95 g (11 mmol) of pivalaldehyde are added dropwise to a solution of0.86 g (10 mmol) of 3-aminopyrrolidine in 10 ml of acetonitrile at roomtemperature in the course of 5 minutes, during which the temperaturerises from 22.5° C. to 27.5° C. The mixture is subsequently stirred for1 hour and a virtually complete conversion into3-(2,2-dimethylpropylideneamino)-pyrrolidine is found by checking thereaction by gas chromatography. The mixture is then diluted with 10 mlof acetonitrile and 10 ml of dimethylformamide, 3 g (10 mmol) of8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-3-quinolinecarboxylicacid and 2.2 g (20 mmol) of 1,4-diazabicyclo 2.2.2!octane are added andthe mixture is heated under reflux for 1 hour. Work up gives the sameresult as described under Example 2a).

EXAMPLE 3 ##STR42##

A) 1.1 g (12.8 mmol) of pivalaldehyde are added to 0.86 g (10 mmol) of3-aminopyrrolidine at room temperature, during which the temperaturerises from 20° C. to 30° C. After 1 hour, the mixture is diluted with 20ml of acetonitrile and 10 ml of dimethylformamide, 3 g (10 mmol) of8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid and 2.2 g (20 mmol) of 1,4-diazabicyclo 2.2.2!octane are then addedand the mixture is heated under reflux for 1 hour. After cooling, theprecipitate is filtered off with suction, washed with acetonitrile anddried at 100° C./12 mbar.

Yield: 3.25 g (75% of theory) of 8-chloro-1-cyclopropyl-7-3-(2,2-dimethylpropylideneamino)-1-pyrrolidinyl!-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid of melting point: 181° C. to 182° C. FAB mass spectrum: m/e 434(100%, M+H.sup.⊕)

¹ H-NMR spectrum (CF₃ COOD): δ1.45 s (9H), 1.25 m and 1.62 m (4H), 2.65m and 2.80 m (2H), 4.2 m and 4.4 m (4H), 4.85 m (1H), 5.02 m (1H), 8.22d (1H), 8.75 s (1H), 9.5 ppm s (1H).

B) 2.3 g (5.3 mmol) of 8-chloro-1-cyclopropyl-7-3-(2,2-dimethylpropylideneamino)-1-pyrrolidinyl!-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid are suspended in 15 ml of water at room temperature and dissolvedwith 10 ml of 1N hydrochloric acid at about 60° C. The solution isfiltered, the filtrate is concentrated under a high vacuum and theresidue is stirred with ethanol. The precipitate is filtered off withsuction and dried in vacuo.

Yield: 1.4 g (65.7% of theory) of7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride, melting point: from 280° C. (with decomposition).

EXAMPLE 4 ##STR43##

Analogously to Example 1, the reaction is carried out with(R)-3-(2,2-dimethylpropylideneamino)-pyrrolidine to give7-(R)-3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid of melting point 252° C.-253° C. (with decomposition)(recrystallized from dimethylformamide).

EXAMPLE 5 ##STR44##

Analogously to Example 1, the reaction is carried out with(S)-3-(2,2-dimethylpropylideneamino)-pyrrolidine to give7-(S)-3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, melting point 253° C.-254° C. (with decomposition).

EXAMPLE 6 ##STR45##

2.8 g (10 mmol) of1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid are heated under reflux with 2.2 g (20 mmol) of 1,4-diazabicyclo-2.2.2!octane and 1.7 g (11 mmol) of3-(2,2-dimethylpropylideneamino)-pyrrolidine in a mixture of 20 ml ofacetonitrile and 10 ml of dimethylformamide for 1 hour. The mixture isconcentrated, the residue is stirred with water, the precipitate isfiltered off with suction and then dissolved in 10 ml ofhalf-concentrated hydrochloric acid, the solution is filtered and thehydrochloride is precipitated with ethanol. The crystals are filteredoff with suction, washed with ethanol and dried at 80° /12 mbar.

Yield: 2.8 g (72.6% of theory) of7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride;

melting point: 305° C.-306° C. (with decomposition).

If the reaction is carried out analogously with3-(3,5-difluorobenzylideneamino)-pyrrolidine, the same product isobtained in a 75% yield.

EXAMPLE 7 ##STR46##

Analogously to Example 6, the reaction is carried out with1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acidto give7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-3-quinolinecarboxylicacid hydrochloride of melting point 301° C.-302° C. (with decomposition)in a yield of 93.6% of theory.

EXAMPLE 8 ##STR47##

1.34 g (11 mmol) of salicylaldehyde are added to 0.86 g (10 mmol) of3-aminopyrrolidine, the mixture is stirred at room temperature for about10 minutes and the viscous reaction product is dissolved in a mixture of20 ml of acetonitrile and 10 ml of dimethylformamide. After addition of2.2 g (20 mmol) of 1,4-diazabicyclo- 2.2.2!octane and 2.65 g (10 mmol)of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, the mixture is heated under reflux for 1 hour and cooled, and thereaction product which has crystallized out is filtered off withsuction, washed with acetonitrile and dissolved in 30 ml ofhalf-concentrated hydrochloric acid. The solution is concentrated, theresidue is stirred with acetonitrile, the undissolved material isdissolved in 30 ml of water under the influence of heat, the solution isfiltered and 100 ml of ethanol are added to the filtrate. Thehydrochloride which has precipitated is filtered off with suction,washed with ethanol and dried.

Yield: 2.6 g (70.7% of theory) of7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-3-quinolinecarboxylicacid hydrochloride;

melting point: 310° C.-317° C. (with decomposition).

The reaction proceeds in an analogous manner if benzaldehyde,2-chlorobenzaldehyde, 3-chlorobenzaldehyde, 2,4-dichlorobenzaldehyde,2-methylbenzaldehyde, 4-methylbenzaldehyde, 4-chlorobenzaldehyde,4-fluorobenzaldehyde or 3,4-difluorobenzaldehyde is used instead of thesalicylaldehyde.

EXAMPLE 9 ##STR48##

A) A mixture of 0.43 g (5 mmol) of 3-aminopyrrolidine and 0.79 g (5.5mmol) of 97% strength 4-chlorobenzaldehyde is stirred without a solventfor 1 hour. It is then diluted with 10 ml of acetonitrile and 5 ml ofdimethylformamide, 1.43 g (5 mmol) of1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecaboxylicacid and 1.1 g of 1,4-diazabicyclo 2.2.2!octane are added and themixture is heated under reflux for 1 hour. It is cooled and theprecipitate which has separated out is filtered off with suction, washedwith acetonitrile and dried at 60° C. in vacuo.

Yield: 2.22 g (94.2% of theory) of 7-3-(4-chlorobenzylideneamino)-1-pyrrolidinyl!-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid;

melting point: 232° C.-237° C.

¹ H-NMR (CF₃ COOD): δ7.75 d and 8.08 d (4H), 8.12 d (1H), 9.07 s (1H),9.3 ppm s (1H)

B) 2.0 g (4.2 mmol) of the product from stage A are dissolved in 35 mlof hot half-concentrated hydrochloric acid, the solution is filtered hotand after cooling, the hydrochloride is filtered off with suction,washed with ethanol and dried.

Yield: 1.34 g (82% of theory) of7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-3-quinolinecarboxylicacid hydrochloride;

melting point: 302° C.-305° C. (decomposition).

EXAMPLE 10 ##STR49##

A) Analogously to Example 9A), the reaction is carried out with3,5-difluorobenzaldehyde and 1-cyclopropyl-6,8-difluoro-7-3-(3,5-difluorobenzylideneamino)-1-pyrrolidinyl!-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid of melting point 225° C.-227° C. (with decomposition) is isolated;

mass spectrum: m/e 473 (M.sup.⊕), 429 (M.sup.⊕ --CO₂), 349, 346, 288;content: 93% pure.

B) The cleavage of stage A with half-concentrated hydrochloric acidproceeds analogously to Example 9B) to give7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-3-quinolinecarboxylicacid hydrochloride,

melting point: 303° C.-306° C. (with decomposition).

EXAMPLE 11 ##STR50##

A) Analogously to Example 9A), the reaction is carried out withbenzaldehyde, followed by isolation of7-(3-benzylideneamino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid of melting point 207° C.-208° C. (decomposition).

¹ H-NMR (d⁶ -DMSO): δ8.6 s (1H), 8.48 s (1H), 7.7 m (3H), 7.45 m (3H),3.65-4.3 m (6H), 2.25 m and 2.05 m (2H), 1.2 ppm m (4H).

B) The cleavage of stage A) with half-concentrated hydrochloric acid iscarried out analogously to Example 9B) to give7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-3-quinolinecarboxylicacid hydrochloride;

melting point: 300° C.-303° C. (with decomposition).

EXAMPLE 12 ##STR51##

A) Analogously to Example 9A), the reaction is carried out withpivalaldehyde followed by isolation of 7-3-(2,2-dimethylpropylideneamino)-1-pyrrolidinyl!-6,8-dilfuoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid of melting point 221° C.-222° C. (with decomposition).

¹ H-NMR spectrum (CF₃ COOD): δ1.46 s (9H), 1.44 m and 1.58 m (4H), 2.63m and 2.75 m (2H), 4.2-4.55 m (5H), 5.0 m (1H), 8.1 dd (1H), 8.79 s(1H), 9.3 ppm s (1H).

B) The cleavage of stage A) with half-concentrated hydrochloric acid iscarried out analogously to Example 9B) to give7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-3-quinolinecarboxylicacid hydrochloride;

melting point: 305° C.-308° C. (with decomposition).

EXAMPLE 13 ##STR52##

A) Analogously to Example 9A), the reaction is carried out withpivalaldehyde and 3-aminomethylazetidine, and 1-cyclopropyl-7-3-(2,2-dimethylpropylideneamino-methyl)-1-azetidinyl!-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid of melting point 254° C.-256° C. (with decomposition) is obtained.

¹ H-NMR (d₆ -DMSO): δ8.57 s (1H), 7.68 s (1H), 7.65 ppm dd (1H).

B) The cleavage of stage A) with half-concentrated hydrochloric acidanalogously to Example 9B) gives7-(3-aminomethyl-1-azetidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-3-quinolinecarboxylicacid hydrochloride, which decomposes at about 200° C.

FAB mass spectrum (positive): m/e 386 (M+HCl+H⁺)⊕!

FAB mass spectrum (negative): m/e 384 (M+Cl⁻).sup.⊖ !.

EXAMPLE 14 ##STR53##

A) A solution of 1.66 g (11 mmol) of 4-nitrobenzaldehyde in 10 ml ofacetonitrile is added to a solution of 0.86 g (10 mmol) of3-aminopyrrolidine in 10 ml of acetonitrile and the mixture is stirredat room temperature for 1 hour. It is diluted with 10 ml ofdimethylformamide, 2.2 g (20 mmol) of 1,4-diazabicyclo 2.2.2!-octane and2.83 g (10 mmol) of1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid are added and the mixture is heated under reflux for 1 hour. Thesuspension is concentrated, the residue is stirred with 60 ml ofacetonitrile and the precipitate is filtered off with suction and driedat 80° C. in vacuo.

Yield: 4.5 g (93% of theory) of1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-3-(4-nitrobenzylideneamino)-1-pyrrolidinyl!-4-oxo-3-quinolinecarboxylicacid.

Melting point: 227° C.-228° C. (with decomposition).

B) 4.3 g (8.9 mmol) of the product from stage A are dissolved in 40 mlof half-concentrated hydrochloric acid, the solution is filtered andconcentrated, the residue is stirred with 30 ml of ethanol and theundissolved precipitate is filtered off with suction, washed withethanol and dried.

Yield: 3.14 g (91% of theory) of7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride;

melting point: 292° C.-294° C. (with decomposition).

EXAMPLES 15 to 19

Analogously to Example 14A), the following are obtained with:

15A) 2-Nitrobenzaldehyde: 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-3-(2-nitrobenzylideneamino)-1-pyrrolidinyl!-4-oxo-3-quinolinecarboxylicacid, melting point: 227° C.-228° C. (with decomposition).

16A) 3-Nitrobenzaldehyde: 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-3-(3-nitrobenzylideneamino)-1-pyrrolidinyl!-4-oxo-3-quinolinecarboxylicacid, melting point: 264° C.-266° C. (with decomposition).

17A) 2,4-Dichlorobenzaldehyde: 1-cyclopropyl-7-3-(2,4-dichlorobenzylideneamino)-1-pyrrolidinyl!-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, melting point: 209° C.-213° C. (with decomposition).

18A) 4-Methylbenzaldehyde: 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-3-(4-methylbenzylideneamino)-1-pyrrolidinyl!-4-oxo-3-quinolinecarboxylicacid,

19A) 4-Methoxybenzaldehyde: 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-3-(4-methoxybenzylideneamino)-1-pyrrolidinyl!-4-oxo-3-quinolinecarboxylicacid.

The compounds of Examples 15A) to 19A) can be reacted analogously toExample 14B) to give7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride.

EXAMPLE 20 ##STR54##

A) A solution of 66.4 g (0.44 mol) of 3-nitrobenzaldehyde in 400 ml ofacetonitrile is added to a solution of 34.4 g (0.4 mol) of3-aminopyrrolidine in 400 ml of acetonitrile and the mixture is stirredat room temperature for 1 hour. It is then diluted with 400 ml ofdimethylformamide, 88 g (0.79 mol) of 1,4-diazabicyclo- 2.2.2!octane and120 g (0.4 mol) of8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid are added and the mixture is heated under reflux (about 91° C. to92° C.) for 1 hour. The resulting suspension is cooled on an ice bathand the precipitate which has separated out is filtered off withsuction, washed with acetonitrile and dried.

Yield: 168.5 g (84.5% of theory) of8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-3-(3-nitrobenzylideneamino)-1-pyrrolidinyl!-4-oxo-3-quinolinecarboxylicacid;

melting point: 204° C.-207° C. (with decomposition).

B) 120 g (0.24 mol) of the product from stage A) are heated under gentlereflux (internal temperature 38° C.) in a mixture of 1.8 l of methylenechloride and 2.4 l of 3N hydrochloric acid for 15 minutes. The mixtureis cooled on an ice bath and the product which has precipitated out isfiltered off with suction, washed thoroughly with acetonitrile and driedin vacuo at 25° C. over KOH.

Yield: 82.7 g (85.5% of theory) of7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclpropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride;

melting point: 279° C.-281° C. (with decomposition) C₁₇ H₁₇ ClFN₃ O₃xHCl (402):

calculated: C 50.7 H 4.5 N 10.4 Cl 17.7 found: C 50.4 H 4.6 N 10.4 Cl17.4

The product contains 0.01% of7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride (8-deschloro derivative).

The 3-nitrobenzaldehyde can be recovered in a virtually quantitativeyield by concentrating the methylene chloride phase.

EXAMPLE 21 to 29

Analogously to Example 20A), the following are obtained with:

21A) 2-Nitrobenzaldehyde: 8-chloro-1-cyclpropyl-6-fluoro-1,4-dihydro-7-3-(2-nitrobenzylideneamino)-1-pyrrolidinyl!-4-oxo-3-quinolinecarboxylicacid, melting point: 234°-237° C. (with decomposition).

22A) 4-Nitrobenzaldehyde: 8-chloro-1-cyclpropyl-6-fluoro-1,4-dihydro-7-3-(4-nitrobenzylideneamino)-1-pyrrolidinyl!-4-oxo-3-quinolinecarboxylicacid, melting point: 207°-210° C. (with decomposition).

23A) 2,4-Dichloro-benzaldehyde:8-chloro-1-cyclpropyl-6-fluoro-1,4-dihydro-7-3-(2,4-dichlorobenzylideneamino)-1-pyrrolidinyl!-4-oxo-3-quinolinecarboxylicacid, melting point: 198°-202° C. (with decomposition).

24A) 2,6-Dichloro-benzaldehyde: 8-chloro-7-3-(2,6-dichlorobenzylideneamino)-1-pyrrolidinyl!-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

25A) 4-Chloro-3-nitro-benzaldehyde: 8-chloro-7-3-(4-chloro-3-nitro-benzylideneamino-1-pyrrolidinyl!-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

26A) 2-Methylbenzaldehyde:8-chloro-1-cyclopropenyl-6-fluoro-1,4-dihydro-7-3-(2-methylbenzylideneamino)-1-pyrrolidinyl!-4-oxo-3-quinolinecarboxylicacid,

27A) 4-Methylbenzaldehyde: 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-3-(4-methylbenzylideneamino)-1-pyrrolidinyl!-4-oxo-3-quinolinecarboxylicacid,

28A) 4-Methoxybenzaldehyde:8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-3-(4-methoxybenzylideneamino)-1-pyrrolidinyl)-4-oxo-3-quinolinecarboxylic acid,

29A) 4-Hydroxybenzaldehyde:8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-3-(4-hydroxybenzylideneamino)-1-pyrrolidinyl!-4-oxo-3-quinolinecarboxylicacid.

The substituted benzylidene protective groups are eliminated under thesame conditions as in Example 20B to give7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylichydrochloride.

EXAMPLE 30

A. A solution of 520 mg (3 mmol) of p-toluenesulphonic acid in 30 ml ofwater are added to 1 g (2 mmol) of the product from Example 20A in 30 mlof methylene chloride and the mixture is heated under reflux for 15minutes. After cooling, the product is filtered off with suction, washedwith ethanol and dried.

Yield: 0.9 g (84% of theory) of7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid p-toluenesulphonate, melting point 222°-225° C. (withdecomposition).

B. 1 g (2 mmol) of the product from Example 20A are heated under refluxin 30 ml of methylene chloride with a solution of 1.8 g of sulphuricacid in 30 ml of water for 1 hour. After cooling, the product isfiltered off with suction, washed with ethanol and dried.

Yield: 0.4 g (48% of theory) of7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid sulphate,

melting point: 210°-215° C. (with decomposition).

EXAMPLE 31 ##STR55##

A. 2.7 g (10 mmol) of1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid areheated under reflux with 2.2 g (20 mmol) of 1,4-diazabicyclo2.2.2!-octane and 1.7 g (11 mmol) of3-(2,2-dimethylpropylideneamino)-pyrrolidine in a mixture of 40 ml ofacetonitrile and 20 ml of dimethylformamide for 1 hour. After cooling,the precipitate which has separated out is filtered off with suction,washed with acetonitrile and dried.

Yield: 3.57 g (88% of theory) of 7-3-(2,2-dimethylpropylidene-amino)-1-pyrrolidinyl!-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, melting point: 250°-252° C. (with decomposition).

B. 3.5 g (8.6 mmol) of the product from stage A is introduced into amixture of 40 ml of 4N hydrochloric acid and 30 ml of methylene chlorideand the mixture is heated under reflux for 15 minutes. After cooling,the product is filtered off with suction, washed with ethanol and dried.

Yield: 2.8 g (87% of theory) of7-(3-amino-1-pyrrolidinyl)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride, melting point: 288°-290° C. (with decomposition).

EXAMPLE 32 ##STR56##

Analogously to Example 31, the following are obtained with1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolonecarboxylic acid:

A. 7-3-(2,2-Dimethylpropylideneamino)-1-pyrrolidinyl!-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, melting point: 262°-268° C. (with decomposition).

B.7-(3-Amino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride, melting point: 290°-292° C. (with decomposition).

EXAMPLE 33 ##STR57##

A. 1.42 g (5 mmol) of1-cyclopropyl-6,7,8-trifluoro-1,4-dichloro-4-oxo-3-quinolinecarboxylicacid are heated under reflux with 1.1 g (10 mmol) of 1,4-diazabicyclo-2.2.2!octane and 920 mg (5.5 mmol) of 3-(2,2-dimethylpropylideneamino)-methyl!-pyrrolidine in 20 ml ofacetonitrile and 10 ml of dimethylformamide for 1 hour. The precipitatewhich has separated out is filtered off with suction, washed withacetonitrile and dried.

Yield: 1.87 g (87% of theory) of 1-cyclopropyl-7-3-(2,2-dimethylpropylideneamino-methyl)-1-pyrrolidinyl!-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, melting point 204°-206° C. (with decomposition).

B. A solution of 1.66 g (11 mmol) of 3-nitrobenzaldehyde in 10 ml ofacetonitrile is added to a solution of 1.0 g (10 mmol) of3-aminomethyl-pyrrolidine in 10 ml of acetonitrile, during which thetemperature of the mixture rises from 21° C. to 24° C., and the mixtureis subsequently stirred at room temperature for 1 hour. It is thendiluted with 10 ml of dimethylformamide, 2.2 g (20 mmol) of1,4-diazabicyclo 2.2.2!octane and 2.83 g (10 mmol) of1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid are added and the mixture is heated under reflux for 1 hour. Theprecipitate is filtered off with suction, washed with acetonitrile anddried.

Yield: 4.7 g (95% of theory) of1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-3-(3-nitrobenzylideneaminomethyl-1-pyrrolidinyl!-4-oxo-3-quinolinecarboxylicacid, melting point: 184°-186° C. (with decomposition).

C. 2.7 g (5.4 mmol) of the product from Example 33B is heated underreflux in a mixture of 40 ml of methylene chloride and 40 ml of 3Nhydrochloric acid for 75 minutes. After cooling, the precipitate isfiltered off with suction, washed with ethanol and dried.

Yield: 1.35 g (62% of theory) of7-(3-aminomethyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride, melting point: 290°-295° C. (with decomposition).

Cleavage of the product from Example 33A with hydrochloric acid givesthe same result.

EXAMPLE 34 ##STR58##

Analogously to Example 33A, the reaction is carried out withtrans-3-(2,2-dimethylpropylideneamino)-4-methylthio-pyrrolidine to give1-cyclopropyl-7- trans-3-(2,2-dimethylpropylideneamino-4-methylthio)-1-pyrrolidinyl!-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, and this is cleaved analogously to Example 32C to give7-(trans-3-amino-4-methylthio-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride, melting point: 255°-257° C. (with decomposition).

EXAMPLE 35 ##STR59##

A. 1.1 g (12.8 mmol) of pivalaldehyde are added to 0.86 g (10 mmol) of3-amino-pyrrolidine at room temperature and after 1 hour the mixture isdiluted with 20 ml of acetonitrile and 10 ml of dimethylformaldehyde.1.1 g (10 mmol ) of 1,4-diazabicyclo- 2.2.21!octane and 3.8 g (10 mmol)of ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate are addedand the mixture is stirred overnight at room temperature. Theprecipitate is filtered off with suction, washed with water and dried invacuo at 100° C.

Yield: 4.25 g (85% of theory) of ethyl 1-(2,4-difluorophenyl)-7-3-(2,2-dimethyl-propylidene-amino)1-pyrrolidinyl!-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylateof melting point: 197°-198° C. (with decomposition).

¹ H-NMR (CDCl₃): δ1.05 s (9H), 1.4 t (3H), 1.9 m und 2.05 m (2H), abroad m at 3.5-3.7 (6H), 4.4 q (2H), 7.05 m (2H), 7.4 m (1H), 8.05 d(1H), 8.35 ppm s (1H).

B. 1.5 g (3 mmol) of the product of step A are heated under reflux in amixture of 15 ml of acetic acid and 12 ml of half-concentratedhydrochloric acid for 6 hours. The mixture is concentrated in vacuo andthe residue is washed with dichloromethane and recrystallized fromglycol monomethyl ether.

Yield: 0.9 g (68% of theory) of7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid hydrochloride of melting point: 275°-283° C. (with decomposition).

It will be appreciated that the instant specification is set forth byway of illustration and not limitation and that various modificationsand changes may be made without departing from the spirit and scope ofthe present invention.

What is claimed is:
 1. A compound of the formula ##STR60## in which R³represents hydrogen, C₁ -C₃ -alkyl, hydroxyl, C₁ -C₃ -alkoxy, C₁ -C₃-alkylthio or halogen,R⁴ represents hydrogen or methyl, R⁵ and R⁶ areidentical or different and represent hydrogen or methyl, m represents 0,1 or 2, n represents 0 or 1 and R' represents hydrogen, straight-chainor branched alkyl having 1 to 10 carbon atoms or phenyl, which canoptionally be substituted by one to five identical or differentsubstituents from the group comprising C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, C₁-C₂ -alkylthio, hydroxyl, nitro, halogen, carboxyl, C₁ -C₄-alkoxycarbonyl, cyano and phenyl, or represents naphthyl, and R"represents hydrogen, straight-chain or branched alkyl having 1 to 5carbon atoms or phenyl, wherein R' and R", together with the carbon atomto which they are bonded, can also form a 5- or 6-membered aliphaticring which is optionally substituted by one or more methyl or ethylradicals.